Arguably the biggest gap preventing progress in treating chronic pulmonary diseases is the lack of a sufficiently sensitive, comprehensive, and non-invasive means to evaluate lung function. Until this gap is filled, patients will receive medications that don't work for them, and development of new therapies will remain expensive, slow, and largely unsuccessful. The long-term goal of our research, therefore, is to develop and implement a means to image all relevant aspects of cardiopulmonary function and structure, non-invasively and longitudinally. Our approach uses hyperpolarized (HP) 129Xe MRI to image ventilation, microstructure, and gas exchange. The objective of this application is to optimize our recently demonstrated capability to image regional gas exchange by 129Xe MRI in human subjects, to use the optimized method to measure and understand resting perfusion heterogeneity, and to demonstrate the sensitivity of this imaging approach to detect changes regional lung function much earlier than currently possible. The central hypothesis is that regional gas exchange is the most sensitive marker of early changes in pulmonary function compared to available means. The rationale for the proposed research is that developing a method that can non-invasively evaluate regional gas exchange will dramatically accelerate research in pulmonary medicine by providing a more sensitive and specific measurement that can be used repeatedly. Thus, the proposed research is relevant to that part of the NIH Mission that pertains to improving health by developing and accelerating the application of biomedical technologies. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three Specific Aims: 1) Optimize 3D blood-selective 129Xe gas exchange MRI 2) Establish image reproducibility as a function of time, posture, and cardiac output, and 3) Image the temporal evolution of regional gas exchange during radiation therapy. Completion of these aims will establish the utility, sensitivity and limitations of this new method compared to gold standards, while positioning it as a sensitive biomarker for research in pulmonary medicine. The first aim is expected to improve the current gas exchange image resolution 8-fold, add specificity for fibrosis, and establish the key MR physics governing the acquisition. The second aim will uncover the key determinants of the resting heterogeneity of 129Xe gas exchange already observed in preliminary studies and establish their reproducibility. The final aim brings these technical and developmental insights together to test the hypothesis that 129Xe MRI will detect alterations in gas exchange earlier than currently available means. The proposed approach is innovative because it exploits the unique properties of HP 129Xe MRI and an innovative acquisition to image lungs' most fundamental function - gas exchange. The proposed research is significant because the imaging method being developed is expected to provide a long-sought window on gas transfer into the pulmonary microcirculation as a harbinger of changing disease status.